Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a-q and 15a-q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a-q and 15a-q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis, cytotoxicity testing, and structure-activity relationships of novel 6-chloro-7-(4-phenylimino-4H-3,1-benzoxazin-2-yl)-3-(substituted)-1,4,2-benzodithiazine 1,1-dioxides

A new series of 16 6-chloro-1,1-dioxo-7-{4-[(4-R(1)-phenyl)imino]-4H-3,1-benzoxazin-2-yl}-3-(substituted amino)-1,4,2-benzodithiazines 7-22 was prepared in order to evaluate the cytotoxic activity against six human cancer cell lines. The structures of the new compounds were confirmed by IR, (1)H-, and (13)C-NMR, elemental analysis and in the cases of 11 and 31 by X-ray crystal structure analysis. This analysis showed that contrary to our earlier report the structures contain a benzoxazine ring instead of the proposed quinazolinone ring. The bioassay indicated that the benzodithiazine derivatives 7-22 possess cancer cell growth-inhibitory properties. Some compounds showed a high level of selectivity for certain cell lines. The most active compounds 11, 12, 16, 19, 21, and 22 exhibited potency higher or comparable to cisplatin. The compounds were particularly effective in LCLC-103H and MCF-7 cell lines with IC(50) values of 0.49-1.60 μM. Quantitative structure activity relationships (QSAR) revealed that a chloro substituent R(1) in the phenyl ring as well as the shape of the substituted amino group at R(2) (e.g., unsaturation is beneficial) are important for potency.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis and evaluation of novel E-2-(2-thienyl)- and Z-2-(3-thienyl)-3-arylacrylonitriles as antifungal and anticancer agents

A series of 3-aryl-2-(2-thienyl)acrylonitriles 7 and 3-aryl-2-(3-thienyl)acrylonitriles 8 were synthesized by the reaction of aromatic aldehydes 6 with 2- and 3-thienylacetonitriles 4 and 5, and evaluated for antifungal and cytotoxic activities against a panel of opportunistic and pathogenic fungi and three different cancer cell lines, respectively.     

Synthesis and antileukemic activity of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)ethanone derivatives

A series of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl) piperidin-1-yl)ethanone derivatives 9(a-e) and 10(a-g) were synthesized and characterized by (1) H NMR, IR, mass spectral, and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Some of the tested compounds showed good antiproliferative activity with IC(50) values ranging from 1.6 to 8.0 μm. Compound 9c, 9e, and 10f with an electron-withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).     

Synthesis of new 3-(3-phenyl-isoxazol-5-yl) or 3-[(3-phenyl-isoxazol-5-yl)-amino] substituted 4(3H)-quinazolinone derivatives with antineoplastic activity

A novel series of 3-(3-phenyl-isoxazol-5-yl) or 3-[(3-phenyl-isoxazol-5-yl)amino] substituted 4(3H)-quinazolinone derivatives was synthesized. The compounds were tested for their antineoplastic activity in vitro against Raji (human Burkitt limphoma). K-562 (human chronic myelogeneous leukemia) and U937 (human histiocytic limphoma) cell lines. The most active quinazolinones showed IC50 values in the range 16-30 microM.     

Design, synthesis, and cytotoxicity of novel 3-arylidenones derived from alicyclic ketones

Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 μm against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.     

Convenient synthesis and antimicrobial activity of new 3-substituted 5-(benzofuran-2-yl)-pyrazole derivatives

The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a, while its reaction with equimolar amount of phenylhydrazine gave ester 3b which then converted to 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 4b. Various new compounds such as imides 5 and 6, acyl hydrazones 7 and 8, bi-pyrazoles 9-12, and 1,3-thiazole derivatives 14 and 15 were prepared from carbohydrazide derivatives 4a, b. The new compounds are tested for their antimicrobial activity. Compounds 2, 5, 7, and 8 showed antifungal activities against C. albicans. Also, compounds 2, 6, 8, and 15 showed antibacterial activities.     

Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.     

Synthesis of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone and their cytotoxic activity

A new series of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone were synthesized via four steps starting from 2-amino-5-methylbenzoic acid and initially screened against A-549 (human non-small cell lung cancer), HCT-8 (human colon cancer), and Bel-7402 (human liver cancer) cell lines at the single concentration of 5 microg/mL using the colorimetric MTT assay. The IC50 values were determined for the compounds reaching > or = 70% inhibition in primary screening by serial dilution. Among the newly synthesized compounds, 9n exhibited potent in vitro cytotoxicity against A-549, HCT-8, and Bel-7402 cell lines with the IC50 values of 1.65, 0.93, and 1.43 microM, respectively.     

Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

The inhibition of cell proliferation by methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) has been studied in vitro against four cell lines selected for their resistance to doxorubicin, cisplatin, taxol and 5-fluorouracil. In previous experiments both compounds showed good in vitro antiproliferative, cytotoxic and pro-apoptotic activities against cell lines of different histologic origin. The results of the experiments presented here suggest that 1-Naph-NMCB is able to overcome all of the different mechanisms of resistance showed by the resistant cell lines used for our experiments. On the contrary, when we used the taxol-resistant A549-T12 cell line, characterized by a mechanism of resistance due to a mutation of the target site of taxol on microtubules, it displayed a partial but significant cross-resistance to 2-Naph-DNB. Although the actual mechanism of this cross-resistance has not yet been definitively elucidated, our results from immunostaining of microtubules suggest that it may be linked to the presence of a shared target site for taxol and 2-Naph-DNB on microtubules.     

Synthesis and in vitro-anticancer and antimicrobial evaluation of some novel quinoxalines derived from 3-phenylquinoxaline-2(1H)-thione

Two novel series derived from 3-phenylquinoxaline-2(1H)-thione 2 and 2-(hydrazinocarbonylmethylthio)-3-phenylquinoxaline 6 have been synthesized. Eight out of twenty six new compounds were selected at the National Cancer Institute for evaluation of their in vitro-anticancer activity. Among them, compounds 3b, 3c, 4b, and 4c displayed moderate to strong growth inhibition activity against most of the tested sub-panel tumor cell lines with GI(50) 10(-5) to 10(-6 )molar concentrations. Compound 4b exhibited a significant value of percent tumor growth inhibition against breast cancer at concentration < 10(-8) M. Compound 4c showed moderate selectivity towards leukemia cell lines with GI(50) of 1.8 to 3.8 microM (selectivity ratio = 5.7). Preliminary antimicrobial testing revealed that compounds 7a, 7b, 8a, 11a, and 11b were as active as ampicillin against B. subtilis (MIC = 12.5 microg/mL). Compounds 7b and 8a were also nearly as active as ampicillin against E. coli (MIC = 12.5 microg/mL). In addition, compounds 4a, 7b, 10b, and 11a were as active as ampicillin against P. aerugenosa (MIC = 50 microg/mL). However, compounds 7b, 8a, and 10b showed mild activity against C. albicans (MIC = 50 microg/mL). The values of minimum bactericidal concentrations indicated that compounds 4a and 7b were bactericidal against B. subtilis and P. aerugenosa, respectively, while compound 10b was bactericidal against both organisms. However, compound 11a was bactericidal against E. coli, P. aerugenosa, and S. aureus.     

反相高效液相色谱法测定(E)-3-(4-((3,5,6-三甲基吡嗪-2-基)甲氧基)-3-甲氧基苯基)丙烯酸在SD大鼠血浆中的浓度

目的 建立测定SD大鼠血浆中(E)-3-(4-((3,5,6-三甲基吡嗪-2-基)甲氧基)-3-甲氧基苯基)丙烯酸浓度的反相高效液相色谱(LC-UV)方法,并用于其在SD大鼠体内的药动学研究。方法 采用Diamonsil-C₁₈(2)柱(100 mm×4.6 mm,5 μm),以乙腈:水(含5 mM的醋酸铵,用醋酸调节pH至4.0)=30:70为流动相,测定70只SD大鼠单剂量尾静脉给药15 mg/kg后不同时刻血浆中药物的浓度,并由此计算其在SD大鼠体内的药动学参数。结果 SD大鼠     

2-(4-三氟甲基苯基)-4-乙基-呋喃-3-酰胺衍生物的设计、合成及其抗肿瘤活性研究

目的 设计、合成新型抗肿瘤的2-（4-三氟甲基苯基）-4-乙基-呋喃-3-酰胺衍生物.方法 以对三氟甲基苯甲醛和丙二酸二乙酯为起始原料,经缩合、环合、酰氯化及胺解等4步反应,合成系列目标化合物.结果 设计合成了15个目标化合物,并对其进行了4种肿瘤细胞A549、QGY、HeLa和SW480的活性测试.结论 显示出较好的抗肿瘤活性,化合物5b显示出最优的高效、广谱抗肿瘤活性,值得深入研究.     

Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents

Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.     

Synthesis and antimicrobial activity of 3-(substituted-phenyl)-sydnones.

3-(3 or 4-Acetylphenyl)-sydnones 7, 8 have been synthesized by formation of the glycines 3, 4, followed by nitrosation to 5, 6 and cyclization with acetic anhydride to sydnones. Sydnone derivatives carrying chalcone moieties 15, 16 were prepared by formation of the chalcone analogues 11, 12 through condensation of the glycines 3, 4 with the appropriate aldehydes, followed by the reactions applied for the preparation of 7, 8. The sydnone derivatives were screened for antimicrobial activities.     

Synthesis and antitumor activity of 1,5,6-substituted E-3-(2-chloro-3-indolylmethylene)-1,3-dihydroindol-2-ones

Synthesis and antitumor activity of new E-3-(2-chloro-3-indolylmethylene)-1,3-dihydroindol-2-ones are described. All compounds prepared were active in the primary test (three human cell lines) and entered the second level (60 human cell lines). The most active antitumor derivatives bear the same substituents in the chloroindole ring and are not CDK1 inhibitors. A COMPARE analysis showed that they could act as tubulin binders. In most cell lines, E-3-(2-chloro-5-methoxy-6-methyl-3-indolylmethylene)-1,3-dihydroindol-2-one was a growth inhibitor more potent than vincristine.     

Dichloro-[1-(hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes: testing on the human ovarian cancer cell lines NIH: OVCAR3 and SK OV 3.

The diastereoisomeric dichloro-[1-(2-, 3- and 4-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes were tested on two human ovarian cancer cell lines NIH: OVCAR-3 and SK-OV-3, both resistant against cisplatin. Dichloro-[threo-1-(3-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) (threo-5-PtCl2) proved to be the most active representative of the new series, producing cytocidal effects at a concentration range of 2.5 to 5.0 microM on the NIH: OVCAR-3 cell line. On the more resistant SK-OV-3 cell line, threo-5-PtCl2 was only moderately active, while in combination with BSO, a GSH level lowering compound, threo-5-PtCl2 showed a strong synergistic effect.     

1-(3-酞酰亚胺基-2-氧丁基)-4-取代苯基哌嗪的合成及抗HIV-1逆转录酶活性

目的合成新型的非核苷类(双杂环苯基)化合物,并观察其抗HIV1-逆转录酶(HIV1-RT)活性。方法以氮芥盐酸盐为起始原料,与不同取代苯胺反应,得到相应的不同取代的哌嗪盐酸盐,并与1-溴-3-酞酰亚胺基-2-丁酮(4)缩合,得到目标化合物。结果合成11个目标化合物(5～15)。经¹HNMR,红外和元素分析确定结构。结论经HIV逆转录酶P-66蛋白测定,化合物11,14,10和13有一定抑制HIV1-RT活性,其IC₅₀分别为29.80,35.20,43.77和63.76 μmol·L^-1。